Despite the recent successes of using immune modulatory antibodies in cancer patients, autoimmune pathologies resulting from the activation of self self-reactive T cells preclude the dose escalations necessary to fully exploit their therapeutic potential. To reduce the observed and expected toxicities associated with immune modulation, here we describe a clinically feasible and broadly applicable approach to limit immune costimulation to the disseminated tumor lesions of the patient whereby an agonistic 4-1BB oligonucleotide aptamer is targeted to the tumor stroma by conjugation to an aptamer that binds to a broadly expressed stromal product, vascular endothelial growth factor (VEGF). The approach was predicated on the premise that by targeting the costimulatory ligands to products secreted into the tumor stroma the T cells will be costimulated prior to their engagement of the MHC/peptide complex on the tumor cell, thereby obviating the need to target the costimulatory ligands to non-internalizing cell cell-surface products expressed on the tumor cells. Underscoring the potency of stroma stroma-targeted costimulation and the broad spectrum of tumors secreting VEGF, in preclinical murine tumor models systemic administration of the VEGF VEGF-targeted 4-1BB aptamer conjugates engendered potent antitumor immunity against multiple unrelated tumors in subcutaneous, post post-surgical lung metastasis, methylcholantrene-induced fibrosarcoma, and oncogene-induced autochthonous glioma models, and exhibited a superior therapeutic index compared to non-targeted administration of an agonistic 4-1BB antibody or 4-1BB aptamer
- Received January 12, 2014.
- Revision received June 5, 2014.
- Accepted June 5, 2014.
- Copyright © 2014, American Association for Cancer Research.